Schistosoma mansoni infection usually peaks in early adolescence and declines in adulthood, a pattern that has led to the hypothesis that individuals in endemic areas can acquire an age-related resistance to reinfection. The acquisition of this immunity is coincident with the natural death of worms, when they release previously inaccessible surface and subsurface schistosome antigens to the immune system. As the antibody response expands with ongoing worm death, a protective immune response evolves overtime. However, an accelerated version of acquired immunity can be induced when individuals experience repeated rounds of treatment with the drug praziquantel (PZQ). We hypothesize that both natural (age-related) and Drug-Induced Resistance (DIR) to S. mansoni reinfection have the following characteristics: (1) antibodies are generated to a repertoire of antigens released by PZQ or worm death and not to a single or a few key antigen(s) and (2) there is a gradual expansion of the antibody repertoire as it evolves with worm death either naturally or by PZQ treatment until resistance is achieved. In TMRC Project 1, we utilize a systems biology approach (immunomics) to explore the evolution of DIR in a cohort of children resident in an area of high S. mansoni tranmission. Recent advances in high-order multiplexing technologies, such as proteome microarrays, enable us to determine the immunomic profile of an individual to an annotated predicted proteome of S. mansoni that contains 1000 proteins. This S. mansoni protein microarray will be used to determine the difference in immunomic profiles of individuals who develop DIR to S. mansoni and age, sex, and exposure-matched individuals who are chronically re-infected with S. mansoni. The kinetics of immunomic profiles of DIR individuals will also be determined. Finally, we plan to combine the individual immunomic profiles with data from from Projects 2 and 3 of the TMRC using a parasite-immune agent mathemtical model for putative drug-effect on resitance (DIR). A key aspect of our strategy is the capacity to identify large populations of antigens recognized by the antibody responses of a well-characterized cohort who display drug-induced resistance to schistosomiasis (DIRs).